Recent studies have revealed that the pathogenesis of various diseases is essentially due to abnormal functions in the apoptosis signal transduction system. Apoptosis modulating therapy is designed to control cell growth and death by inducing or suppressing apoptosis, with the aim of fundamentally reversing diseases by converting abnormal cells to normal ones as well as halting the progression of diseases by the apoptosis of abnormal cells. Hence, a technology controlling reversibly cell survival-death accounts for the next generation of core technology for apoptosis modulating therapy.
Apoptosis modulating therapy, which is now competitively being developed across the world, can find applications in the treatment of various diseases including leukemia, cancer, AIDS, and senile and degenerative diseases such as Alzheimer's disease, Parkinson's disease, and aging. However, apoptosis modulating therapy is arising as a fundamental technique applicable to a wider spectrum of diseases as abnormal functions of the apoptosis signal transduction system are revealed to account for the onset of most diseases.
Designed to either suppress the pathological uncontrollable growth of cells such as cancerous cells or to prevent normal cells from undergoing excessive cell death as in degenerative diseases such as Alzheimer's disease or Parkinson's disease, apoptosis modulating therapy can be used in the therapy of diseases. For cancer, for example, conventional chemotherapy, characterized by causing necrosis over a wide range of cells, not only kills pathological cells, but also exhibits cytotoxicity to normal cells with the concomitant induction of excessive inflammation, as cytotoxic enzymes (e.g., lysozymes) are released upon the lysis of the pathological cells. By contrast, apoptosis modulating therapy induces pathological cells to undergo apoptosis or strongly suppresses the growth of pathological cells without the inflammatory side effects caused by the necrosis of cancer cells. When cells are under the potent effect of growth inhibition, cancer cells are more greatly restrained from growing than are normal cells because of the greater proliferative activity of cancer cells. If this inhibitory effect is maximized to induce apoptosis, various cytotoxic intracellular factors are for the most part digested by caspase during apoptosis to lose their functions while being surrounded by apoptotic bodies and subsequently phagocytosed by macrophages. During phagocytosis, the cytotoxic factors are neither released extracellularly nor exert cytotoxicity on surrounding cells.
Programmed cell death (apoptosis) is active death of a cell requiring energy, with the accompaniment of characteristic morphological changes. Given an apoptotic signal, a cell is triggered to destroy itself and commits suicide. In this phase, the cell undergoes biochemical events which lead to morphological changes. Once apoptosis proceeds, cells shrink and separate from adjacent cells, showing membrane blebbing, chromatic condensation, and chromosomal DNA fragmentation and forming apoptotic bodies that phagocytic cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage. Apoptosis is a complex intracellular process. Although not easily determined, apoptosis may be achieved via various downstream pathways once it is triggered. Caspases, which are aspartic acid specific cysteine proteases, are responsible for most morphological changes which take place during apoptosis.
Albumin is a multifunctional protein which is most abundantly found in blood plasma. This plasma protein is produced mainly in the liver and is a major component of most extracellular fluids including interstitial fluid, lymph, and cerebrospinal fluid. Since a reduced level of albumins may lead to hepatic dysfunction and malnutrition, albumin has been extensively used for critical conditions including vascular collapse in serious patients or hepatic cirrhosis patients in clinics. In addition, recent research has suggested that albumin specifically binds to low-molecular weight molecules that might be important diagnostic or prognostic indicators of diseases. For example, albumin is reported to enter the brain across the blood-brain barrier by molecular diffusion and also to be implicated in Alzheimer's disease because it can specifically bind to and transport amyloid beta 1-42 (Aβ1-42). The present inventors reported in 2008 the finding that albumin can be synthesized in microglial cells, a kind of cells of the mononuclear phagocyte system, in the brain and that the synthesis and extracellular secretion of albumin from microglial cells increases upon microglial activation with Aβ1-42 [Ahn S-M, Byun K, Cho K, Kim J Y, Yoo J S, et al. (2008) Human Microglial Cells Synthesize Albumin in Brain. PLoS ONE 3(7): e2829].
Advanced glycation end-products (AGEs) are complex products which are incessantly produced inside the body mainly by reactions between carbohydrates and free amino acids. AGEs are chemically very unstable and reactive and are known as potent molecules that promote neuronal cell death. AGEs are also reported to be found in increased levels in the brain of senile persons or animals, and to exert influences on all cells and biological molecules, causing senescence and senescence-related chronic diseases. That is, AGEs are involved in senescence, Alzheimer's disease, renal disease, diabetes mellitus, diabetic vascular complications, diabetic retinopathy and diabetic neuropathy, due to enhancing vascular permeability, suppressing vasodilation via nitrogen oxide interference, and increasing LDL oxidation, the release of various cytokines from phagocytes or endothelial cells, and oxidative stress.
Since AGEs are found, as described above, at an elevated level in the brain of senile persons or animals, many scientists have suggested that AGEs might have influences on neurodegenerative diseases such as Alzheimer's disease by promoting neuronal cell death. In spite of extensive research results, the precise synthesis mechanism or main secretion places of AGEs still remain unknown.
Hence, the discovery of the precise synthesis mechanism and origin of AGEs may be helpful in finding a method for inhibiting the induction of cell death, thus contributing a clue to the etiology of various diseases. There is therefore a need for researching the precise synthesis mechanism of AGEs by which the pathology of various diseases can be revealed.